Zou Menglin, Zheng Weishuai, Hu Xingxing, Gao Han, Hou Qinhui, Song Weiwei, Liu Yuan, Cheng Zhenshun
Department of Respiratory and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China; Fourth Ward of Medical Care Center, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, China.
Department of Respiratory and Critical Care Medicine, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, China.
Int J Biol Macromol. 2025 May;307(Pt 1):141890. doi: 10.1016/j.ijbiomac.2025.141890. Epub 2025 Mar 8.
Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by myofibroblasts accumulation and uncontrolled extracellular matrix (ECM) deposition. Here, we reported that activating transcription factor 4 (ATF4), a multifunctional transcription regulatory protein, is overexpressed in IPF lungs and mouse fibrotic lungs, mainly in myofibroblasts and macrophages. Haplodeletion of Atf4 in mice or blockage of Atf4 with Atf4 shRNA-loaded lentiviruses in mice reduced bleomycin (BLM)-induced pulmonary fibrosis (PF) in vivo. Mechanistically, we found that ATF4 directly binds to the promoter of Acta2 (encodes α-SMA), and promotes lung fibroblasts activation and myofibroblasts accumulation. Additionally, ATF4 regulates macrophage M2 program, and promotes TGFβ1 secretion by directly influencing Tgfb1 gene expression in macrophages, subsequently enhances crosstalk between macrophages and lung fibroblasts. These data suggest that strategies for inhibiting ATF4 may represent an effective treatment for PF.
特发性肺纤维化（IPF）是一种破坏性疾病，其特征是肌成纤维细胞积聚和细胞外基质（ECM）不受控制地沉积。在此，我们报道了激活转录因子4（ATF4），一种多功能转录调节蛋白，在IPF肺组织和小鼠纤维化肺组织中过表达，主要存在于肌成纤维细胞和巨噬细胞中。小鼠Atf4单倍体缺失或用负载Atf4 shRNA的慢病毒在小鼠中阻断Atf4可减轻博来霉素（BLM）诱导的体内肺纤维化（PF）。从机制上讲，我们发现ATF4直接结合Acta2（编码α-SMA）的启动子，并促进肺成纤维细胞活化和肌成纤维细胞积聚。此外，ATF4调节巨噬细胞M2程序，并通过直接影响巨噬细胞中Tgfb1基因表达促进TGFβ1分泌，随后增强巨噬细胞与肺成纤维细胞之间的相互作用。这些数据表明，抑制ATF4的策略可能是治疗PF的有效方法。
